There is a world-wide effort to develop effective anti-viral strategies against HIV-1 for the prevention and intervention of the human AIDS epidemic. We have used two approaches to develop HIV-1 antivirals: a recombinant antisense plasmid DNA that can transcribe antisense RNAs to inhibit HIV-1 replication; and a plasmid DNA vaccine which can potentially generate immune responses to prevent HIV-1 infection. In vitro studies indicate that the recombinant antisense plasmid DNA can inhibit HIV-1 replication of selected T-cell-tropic and macrophage-tropic isolates that represent the spectrum of viruses occurring in North America. Current efforts are underway to develop an efficient packaging cell system for delivery in vivo. Studies of the HIV-1 vaccine DNAs indicate expression of the gag and env genes present in the construct and development of humoral and cellular immune responses in monkeys. Safety assessment of both antiviral constructs will be also be conducted to evaluate potential human risk using these novel approaches. Major research efforts are underway worldwide to develop antiviral agents against HIV-1 for the prevention and intervention of the human AIDS epidemic. The areas of antisense DNAs and plasmid DNA vaccines are novel and rigorously being pursued as potential therapeutics and vaccine strategies against HIV-1. Our laboratory research in these areas prepare us to actively provide guidance and expert review in related products submitted to the FDA for evaluation.